medwireNews: The addition of the androgen receptor (AR) inhibitor enzalutamide to the aromatase inhibitor exemestane may improve the progression-free survival (PFS) of a subset of patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer, study data suggest.
Specifically, treatment-naïve patients with high AR levels, low ESR1 levels, or both derived a PFS benefit from the enzalutamide–exemestane duo relative to exemestane alone.
The phase 2 study included 127 postmenopausal patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer who had not received prior endocrine therapy for advanced disease (cohort 1) and another 120 patients who had progressed after at least one prior endocrine therapy (cohort 2). Participants were randomly assigned to receive either enzalutamide 160 mg/day alongside exemestane 50 mg/day or placebo plus exemestane 25 mg/day.
As reported in Clinical Cancer Research, the addition of enzalutamide to exemestane did not significantly prolong PFS among patients in the intent-to-treat population of either cohort, at a median of 11.8 versus 5.8 months with enzalutamide versus placebo in cohort 1, and 3.6 versus 3.9 months in cohort 2.
An exploratory analysis of mRNA sequencing data revealed that cohort 1 patients with high levels of AR (above the median value) derived a significant PFS benefit from the addition of enzalutamide to exemestane, with a median PFS of 14.0 months versus 5.5 months with exemestane alone (hazard ratio [HR]=0.42). This was also the case for participants with low ESR1 (below the median) levels, with corresponding median PFS durations of 11.8 and 3.8 months (HR=0.52).
Of note, patients in cohort 1 who had both high levels of AR and low levels of ESR1 “appeared to derive a particularly large benefit from the combination of enzalutamide and exemestane,” report Ian Krop (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and colleagues. The median PFS in this subgroup of patients was 14.0 months with the combination versus 3.8 months with exemestane alone, giving a significant HR of 0.24.
“In contrast, patients with high ESR1 and low AR levels perform better on exemestane alone, consistent with the notion that ER [estrogen receptor] signaling is more functionally relevant in these patients; although, paradoxically, they have reduced benefit when enzalutamide is added to exemestane,” add the researchers.
The relationship between AR and ESR1 expression and PFS benefit with enzalutamide did not extend to patients who had previously received endocrine therapy, which the study authors speculate may be due to the fact that “[t]hese patients’ tumors may have developed resistance mechanisms reliant on alternative pathways less dependent on AR or ER signaling.”
Reporting on the safety, the researchers say the combination was “well tolerated,” even though treatment-emergent adverse events (TEAEs) of grade 3 or higher were observed in more patients in the combination than exemestane alone groups, at rates of 32.3% versus 23.8% in cohort 1 and 36.7% versus 20.0% in cohort 2.
The most common TEAEs of grade 3 or more in cohort 1 were hypertension (9.7 vs 3.2% with combination and exemestane alone, respectively) and hypercalcemia (3.2 vs 1.6%), whereas anemia (6.7 vs 3.3%), fatigue (5.0 vs 0.0%), and headache (5.0 vs 0.0%) were most common in cohort 2.
Krop et al conclude: “The role of the AR in HR[-positive] breast cancer, the predictive value of the identified biomarkers, and appropriate sequencing with other effective agents are still unclear and will require further studies.”
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