Emerging data with CDK4/6 inhibitors and antibody-drug conjugates (ADCs) challenge assumptions about treatment resistance and are emblematic of a rapidly evolving hormone receptor–positive breast cancer treatment paradigm, according to Rena D. Callahan, MD.
In an interview with OncLive®, Callahan noted the potential clinical implications of data from the phase 3 postMONARCH trial (NCT05169567), which showed a significant progression-free survival (PFS) improvement with abemaciclib (Verzenio) plus fulvestrant (Faslodex; n = 182) vs placebo plus fulvestrant (n = 186) in patients with hormone receptor–positive, HER2-negative advanced breast cancer who had progressed on a prior CDK4/6 inhibitor plus endocrine therapy (HR, 0.73; 95% CI, 0.57-0.95; P = .017).1
She also noted questions that remain regarding sequencing ADCs in hormone receptor–positive disease. The agent fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is FDA approved for the treatment of patients with unresectable or metastatic hormone receptor–positive, HER2-low or -ultralow breast cancer who have progressed on at least 1 endocrine therapy in the metastatic setting.2 Following this line of therapy, more data are needed to determine the roles of other ADCs, such as datopotamab deruxtecan-dlnk (Dato-DXd; Datroway)—approved for patients with unresectable or metastatic hormone receptor–positive, HER2-negative disease who have received prior endocrine therapy and chemotherapy, as well as sacituzumab govitecan-hziy (Trodelvy)—approved for patients with this disease who have received endocrine therapy and 2 or more additional systemic therapies in the metastatic setting.3,4
She highlighted additional facets of hormone receptor–positive breast cancer management, including CDK4/6 inhibitors, circulating tumor DNA–prompted therapeutic switches, and oral selective estrogen receptor degraders (SERDs), in another part of the interview.
Callahan is a breast medical oncologist at UCLA Health and an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California.
OncLive: Based on data from postMONARCH, what might be the role for continued CDK4/6 inhibition following progression on a prior CDK4/6 inhibitor in patients with hormone receptor–positive, HER2-negative advanced breast cancer?
Callahan: Now we’ve had a few years to sit with the data. [These] phase 3 data were a nice addition to the phase 2 data from the MAINTAIN trial [NCT02632045] with ribociclib [Kisqali]. For years, there was the sense that CDK4/6 inhibition after CDK4/6 inhibition would not work, that once a patient was treated with a drug in that class, there is resistance, and they could not benefit from another. These trials were important to prove that wrong.
However, there are some nuances in the trials that are important. [For example,] postMONARCH was a trial of patients who were initially treated with palbociclib [Ibrance] and then were switched to abemaciclib plus fulvestrant. How to apply that to how we currently treat patients can be a little tricky. Most of us are treating in the first-line setting with ribociclib and some with abemaciclib, less so with palbociclib. How to apply these data to patients who are treated with ribociclib or abemaciclib first is a question we don’t fully have the answer to. However, most of us use this strategy for appropriate patients.
Who are the appropriate patients in our practices? Sometimes they are a patient with disease progression that is not [characterized by] endocrine resistance or lots of visceral disease lab abnormalities, or someone who you may not know had disease progression unless you saw it on a scan. For those patients, many of us want to continue their generally high quality of life, and we can achieve that often by giving a CDK4/6 inhibitor after a CDK4/6 inhibitor and potentially switching the endocrine therapy. With the [potential upcoming] combination approval of [CDK4/6 inhibition plus an] oral SERD, we will hopefully have that as an option as well.
How might the role of ADCs continue to evolve in hormone receptor–positive breast cancer management?
We’ve seen ADCs in hormone receptor–positive disease beat chemotherapy, and with T-DXd, we’ve even seen this in the chemotherapy-naive setting. We’re moving ADCs further up in lines of treatment. We generally have [multiple] ADCs to choose from for hormone receptor–positive disease.
Based on the available data, most of us will reach for T-DXd in the earlier-line setting and then use one of the other 2 ADCs that are FDA approved: Dato-DXd or sacituzumab govitecan. We still don’t know how to sequence these ADCs, so we’re [learning] as we go along. Sometimes we’re sandwiching chemotherapy between ADCs, but we don’t have level one data to help us make those decisions yet. Hopefully, with ongoing trials, we will learn more about sequencing ADCs, and over time, we will have different ADCs to choose from.
A New Era of Hormone Receptor–Positive Breast Cancer Management
- Recent clinical data from the postMONARCH and MAINTAIN trials demonstrate that switching to a different CDK4/6 inhibitor after initial disease progression can be an effective strategy to extend treatment benefit and maintain quality of life.
- ADCs are being moved into earlier lines of therapy because they have shown superior efficacy compared with traditional chemotherapy, even in patients who have not previously received chemotherapy.
- Although breast medical oncologists currently have multiple effective ADCs to choose from, ongoing research is focused on determining the optimal sequencing of these treatments and developing next-generation therapies to further improve survival outcomes.
There are a lot of similarities between the 3 ADCs we currently have regarding payload, [by] targeting topoisomerase I. Also, the antibody portions of the ADCs are similar, [such as] TROP2 for Dato-DXd and sacituzumab govitecan. To get outside that box with next-generation ADCs is a direction we’ll be looking toward.
Overall, what is your outlook on the future of breast cancer research?
I’m always impressed by how much things change in a short period of time. Whenever I meet a new patient, when we talk about things like overall survival and PFS, I reinforce what is [true] today, and that if we have the same conversation a few years from now, there will be new therapies, and those new therapies generally come with longer survival. It’s exciting. It’s a great time to be a breast cancer doctor.
References
- Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase III postMONARCH trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086
- Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News Release. AstraZeneca. January 27, 2025. Accessed April 28, 2026. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
- FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed April 28, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast
- US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences. February 3, 2023. Accessed April 28, 2026. https://www.gilead.com/news/news-details/2023/us-fda-approves-trodelvy-in-pre-treated-hrher2--metastatic-breast-cancer
