Evaluating an ER Degrader for Breast Cancer Free

Results from a first-in-human phase I/IIa study of the investigational compound GDC-0810 (Genentech) indicate that this selective estrogen receptor degrader (SERD) is tolerable and may benefit some postmenopausal women with advanced estrogen receptor (ER)–positive breast cancer. The trial data were presented by Maura Dickler, MD, an associate member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York, NY, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22.

Modulating estrogen's activity and synthesis continues to be the main therapeutic strategy for ER-positive disease, which accounts for up to 70% of breast cancers. However, resistance to hormonal therapies like tamoxifen often develops through a variety of mechanisms, including ESR1 mutations that activate the ER even in the absence of estrogen. As such, new treatments for these relapsed patients are “urgently needed,” Dickler said—drugs that, like GDC-0810, not only bind to and antagonize the ER, but also induce conformational changes leading to receptor degradation.

In preclinical studies, Dickler and her colleagues observed tumor regression in mice treated with GDC-0810, but not in those given tamoxifen or another SERD, fulvestrant (Faslodex; AstraZeneca). PET imaging with ¹⁸F-fluoroestradiol (FES), which binds to the ER, showed significantly lower tracer uptake in mice given GDC-0810, compared to control animals.

The researchers then enrolled 41 postmenopausal women with advanced ER-positive breast cancer whose disease had progressed after at least 6 months of endocrine therapy. The patients were given GDC-0810 once or twice daily, with or without food. Common side effects included diarrhea, nausea, and fatigue—mostly mild to moderate in severity, Dickler said, noting that food intake improved the drug's gastrointestinal tolerability. FES-PET imaging showed that GDC-0810 competed effectively with the tracer and occupied the ER at all doses tested, even in patients with ESR1 mutations, “supporting robust target engagement,” she added.

Fourteen of 37 evaluable patients (38%) remained on treatment without disease progression for more than 24 weeks. Dickler also reported that two patients with ESR1-mutant tumors and liver metastases had confirmed partial responses to GDC-0810. The drug is undergoing further evaluation in a phase II study, at a recommended dose of 600 mg once daily with food.

To gain ground on endocrine therapy resistance, “we really need a way to get rid of the ER itself, or at least reduce it to very low levels,” said Kent Osborne, MD, director of Baylor College of Medicine's Cancer Center in Houston, TX. He noted that, like fulvestrant, GDC-0810 only partially degrades the ER, “which is not optimal.”

Osborne also expressed concern over GDC-0810′s gastrointestinal tolerability. “Even low-grade side effects can be important to consider for patients who may be on this therapy for years,” he pointed out, while acknowledging that “determining the best dose is always challenging with endocrine agents.”

Overall, Osborne considered this new SERD “potentially exciting, with encouraging early data,” especially in ESR1-mutant disease. “I thought a few years ago that we knew everything about the ER,” he remarked, “but new strategies to block its activity are still being revealed as we learn more about how estrogen works in cells.”