Androgen Receptor Agonist Active in Resistant ER+ Breast Cancer

MIAMI BEACH — A first-in-class androgen receptor (AR) agonist led to clinically meaningful objective response rates in patients with heavily treated estrogen receptor (ER)-positive breast cancer, a preliminary trial showed.

Overall, 30% of patients obtained clinical benefit from either of two doses of enobosarm. Half of a small subgroup of patients with palbociclib (Ibrance)-resistant disease benefited from the treatment, including a 30% objective response rate. Patients with AR expression ≥40% appeared to derive greater benefit (43% response rate vs 0% for AR expression <40%), although the data came from a total of 10 patients, as reported here at the Miami Breast Cancer Conference.

“Enobosarm AR-targeted treatment demonstrated clinical benefit with objective tumor responses in women with heavily pretreated estrogen blocking agent-resistant, AR+, ER+, HER2- metastatic breast cancer,” reported Elgene Lim, MD, PhD, of the Garvan Institute of Medical Research in Darlinghurst, Australia, and colleagues, in a poster presentation. “Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK4/6 inhibitor.”

“Quality-of-life measurements demonstrated overall improvement, including mobility, anxiety/depression, and pain. Enobosarm appears safe and well tolerated without masculinizing effects, increase in hematocrit, or liver toxicity,” the team said.

In as many as 95% of breast cancers, AR is the most highly expressed steroid hormone receptor. However, its role in breast cancer evolution has remained unclear. Preclinical evidence indicated that androgens inhibit cellular proliferation. Multiple studies have shown that AR positivity is an independent predictor of better breast cancer outcomes, the investigators noted.

In preclinical and preliminary clinical evaluations, enobosarm exhibited greater inhibition of estrogen blocking agent-resistant breast cancer than did a CDK4/6 inhibitor. The combination of enobosarm and a CDK4/6 inhibitor achieved greater inhibition than either agent alone.

Lim and colleagues reported findings from a phase II trial of 136 patients with previously treated metastatic AR+/ER+ breast cancer. Patients received either 9 mg or 18 mg of oral enobosarm daily, and the primary endpoint was clinical benefit rate (CBR) at 24 weeks. In 102 evaluable patients, the 9-mg dose resulted in a CBR of 32% and the 18-mg dose a CBR of 29%.

Enobosarm was well tolerated, the investigators reported, as the most common grade 3/4 adverse events in all 136 patients were increased liver enzymes (five patients total), hypercalcemia (four patients), and fatigue (three patients).

The results supported an ongoing phase III trial of enobosarm 9 mg plus abemaciclib (Verzenio) in patients with previously treated AR+/ER+ metastatic breast cancer and AR staining ≥40%. Eligible patients must have received a nonsteroidal aromatase inhibitor plus palbociclib or fulvestrant plus palbociclib for metastatic disease.

Activity in Uncommon HER2-Mutant Breast Cancer

In another poster study at the meeting, a three-drug combination demonstrated preliminary activity in advanced/metastatic breast cancer associated with HER2 mutations in the absence of HER2 amplification or protein overexpression.

Data from a nonrandomized cohort showed that 12 of 26 patients (46.2%) with HR+/HER2-/HER2-mutant disease achieved partial responses to the combination of neratinib (Nerlynx), trastuzumab (Herceptin), and fulvestrant. All the patients had prior exposure to CDK4/6 inhibitors. Additionally, a neratinib-trastuzumab doublet therapy led to objective responses in six of 18 patients with HER2-mutant triple-negative breast cancer (TNBC), including one complete response.

A randomized cohort of 21 patients with HR+/HER2-/HER2-mutant disease showed no clinical activity with fulvestrant alone or fulvestrant plus trastuzumab, whereas three of seven patients responded to the three-drug combination. The observation suggests that the HER2-targeted agent neratinib “appears to be critical for inhibition of HER2 mutations,” reported Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-investigators.

Diarrhea was the most common adverse event associated with the three-drug combination, occurring in 30 of 33 patients and reaching grade 3/4 severity in 15 patients. Three patients each had grade 3/4 vomiting, fatigue, and decreased appetite. Grade 3/4 diarrhea and fatigue occurred in three of 18 patients with TNBC treated with neratinib and trastuzumab.

Enrollment continued to a total of 50 patients with HR+/HER2-/HER2-mutant breast cancer treated with neratinib, trastuzumab, and fulvestrant, and enrollment is ongoing in the TNBC study, the investigators reported.

HER2 mutations in the absence of amplification or protein overexpression is an uncommon mechanism of oncogenic addiction to HER2 signaling. Preclinical evidence suggested that resistance to ER-directed therapy could be overcome with the addition of neratinib.