Lasofoxifene Combination Therapy Shows Promise for Treatment-Resistant Breast Cancer

Endocrine therapy is a standard treatment for ER-positive, HER2-negative metastatic breast cancer. Long-term, however, this treatment can lead to resistance that makes the cancer very hard to treat. Now a new combination therapy shows promise as a safe and effective treatment option for these patients.

In a phase 2 clinical trial, researchers gave a combination of lasofoxifene and abemaciclib to patients with metastatic breast cancer whose disease had progressed after prior treatment. Patients had a good response rate, with median progression-free survival of more than a year.

“For this population of patients, that’s quite remarkable,” says Halle Moore, MD, Director of Breast Medical Oncology at Cleveland Clinic and coauthor of the study. “If these results can be reproduced in a larger phase 3 trial, this is a potentially practice-changing combination.”

Targeting ESR1 mutations

Endocrine resistance in these cancers is linked to a genetic mutation called ESR1. Cancers that develop this mutation become much more difficult to treat. Preclinical studies showed that lasofoxifene worked by targeting these mutations, and was even more potent when used in combination with a CDK46 inhibitor like abemaciclib.

For the new trial, researchers tried the combination therapy in 29 patients. Of these, all had previously received endocrine therapy, and all but one had previously been treated with a CDK46 inhibitor. Half had also received chemotherapy.

“These are patients who have had a lot of prior treatment,” Moore says. Almost 70% of patients saw a clinical benefit at 24 weeks of treatment, and median progression-free survival was 56 weeks.

Toxicities included nausea, vomiting, diarrhea and fatigue, all of which are known side effects of abemaciclib. One side effect of concern was thrombosis, which is a potential side effect of both abemaciclib and lasofoxifene. Thrombosis developed in roughly 10% of patients. However, most of these patients also had a response to treatment and were able to continue with anticoagulation medication.

Importantly, researchers also took blood samples from patients to measure circulating tumor DNA containing the ESR1 mutation, and found that 81% decreased or even became undetectable.

“It suggests that we are targeting the ESR1 mutation as part of this treatment, and it’s nice to see a clearing of the circulating tumor DNA that may also be indicative of a response to treatment,” says Dr. Moore.

Limitations include the study’s size and single-arm design. “Even so, these patients represent a group for whom we would not have expected results this good with an endocrine-based approach,” she says. Next, researchers have designed a phase 3 trial which they hope to open soon. The study findings have been presented at the American Society of Oncology (ASCO) annual meeting and the San Antonio Breast Cancer Symposium. Full manuscript publications are anticipated soon.