Enobosarm Induces a 50% CBR in AR+/ER+ Metastatic Breast Cancer That Has Progressed on Palbociclib

Carlo Palmieri, BSc, MBBS, PhD, FRCP

The nonsteroidal selective androgen receptor (AR) agonist enobosarm has been shown to induce a clinical benefit rate (CBR) of 50% at 24 weeks in evaluable patients with measurable metastatic AR-positive, estrogen receptor (ER)–positive, metastatic breast cancer that has progressed on treatment with the CDK4/6 inhibitor palbociclib (Ibrance), according to data from a phase 2 G200802 trial.¹

Results presented during the ESMO Breast Virtual Congress 2021showed that the CBR at 24 weeks in evaluable patients who received the 9-mg dose of the agent (n = 50) was 32% (95% CI, 19.5%-46.7%) vs 29% (95% CI, 17.1%-43.1%) in those who received the 18-mg dose of the agent (n = 52). The median radiographic progression-free survival (rPFS) in the 9- and 18-mg cohorts was greater than 5.6 months (range, 0-27.5) and 4.2 months (range, 0-16.5), respectively.

Moreover, the best objective tumor response (BOR) in patients who had progressed on endocrine therapy and a CDK4/6 inhibitor in the metastatic setting was 30%, and this included 2 complete responses (CRs) and 1 partial response (PR). The overall mean rPFS was 10.0 months in those who received the agent at a dose of 9 mg; in the 9-mg and 18-mg cohorts combined, the mean rPFS was 7.3 months.

Among 34 patients with measurable disease at baseline in the 9-mg cohort, the BOR per central read and RECIST v1.1 criteria, at any time during the study, was 29.4% (n = 10); this included a CR rate of 5.9% (n = 2) and a PR rate of 23.5% (n = 8). In 37 patients with measurable disease at baseline in the 18-mg cohort, the ORR was 24.3% (n = 9), with an 8.1% CR rate (n = 3) and a 16.2% PR rate (n = 6).

Androgens have historically been utilized in the treatment of patients with breast cancer; however, their virilizing effects have limited their clinical application in this population. In patients with ER-positive disease, AR agonists have been shown to hinder tumor growth. The majority of breast cancers, 70% to 95%, have AR positivity. Moreover, a high concordance rate of 70% has been observed between AR positivity in primary and metastatic lesions.

“AR positivity is an independent predictor of beneficial breast cancer outcome,” lead study author Carlo Palmieri, BSc, MBBS, PhD, FRCP, of The Clatterbridge Cancer Center NHS Foundation Trust, and colleagues, wrote in a poster on the data. “The development of novel strategies to target the AR as a treatment for women with ER-positive breast cancer that have exhausted drugs that target the ER is warranted.”

Enobosarm was developed to have selectivity for AR without cross-reactivity or binding to other steroidal hormone receptors. Because it is not a substrate for aromatase, the agent cannot be aromatized to estrogen. The agent was designed to build and heal bone and it possesses the potential to treat patients with antiestrogen-induced osteoporosis and help to prevent skeletal-related effects.

Previously, enobosarm has been shown to inhibit AR-positive/ER-positive breast cancer in cell and patient-derived xenograft models of endocrine-sensitive and -resistant disease, according to the study investigators.

Specifically, single-agent enobosarm was found to have greater inhibition of breast cancer that was resistant to an ER-targeting agent vs a CDK4/6 inhibitor in preclinical models. Moreover, when combined with a CDK4/6 inhibitor, the agent was found to have stronger inhibition of ER-targeting agent–resistant breast cancer vs either drug alone. In breast cancer cells that were resistant to both CDK4/6 inhibition and an ER-targeting agent, enobosarm was found to suppress breast cancer cells.

When paired with a CDK4/6 inhibitor, enobosarm further suppressed breast cancer cells that were resistant to both CDK4/6 inhibition and an ER-targeting agent; in fact, enobosarm was found to restore sensitivity to CDK4/6 inhibitors.

In the open-label, multicenter, parallel-design phase 2 G200802 trial, investigators set out to examine the safety and efficacy of oral enobosarm at a daily dose of either 9 mg (n = 72) or 18 mg (n = 64) in postmenopausal patients with AR-positive, ER-positive metastatic breast cancer.

To be eligible for enrollment, patients had to have metastatic or locally recurrent disease that was not amenable to surgery and they needed to have previously responded to adjuvant endocrine treatment for at least 3 years or more endocrine treatment for metastatic disease for 6 months or longer. The primary end point of the trial was CBR at 6 months via RECIST v1.1 criteria and biomarkers were also evaluated, including serum prostate-specific antigen and circulating tumor cells.

Baseline characteristics proved to be comparable between the 2 treatment cohorts.² The median age of study participants in the 9-mg cohort was 60.5 years, while it was 62.5 years in the 18-mg cohort. More than half of the patients had an ECOG performance status of 0; this was true for 60.0% of those in the 9-mg arm and 53.8% of those in the 18-mg arm. Moreover, most patients in the 9- and 18-mg cohorts had previously received chemotherapy (90.0% and 92.3%, respectively). The median prior lines of endocrine therapy received was 3.2 (range, 1-7) in both treatment arms.

Additionally, EuroQoL-visual analogue scale (EQ-VAS) scores were obtained at baseline and during the study, at week 24 and end of therapy (EOT). For the entire instrument, a 8.6 (14.69; P = .002) improvement from baseline to EOT was observed in the 9-mg cohort vs 7.3 (16.67; P = .011) in the 18-mg cohort.

Specifically, in the 9- and 18-mg cohorts, the percentage of patients who experienced an improvement at week 24 in terms of mobility was 40% vs 50%, respectively; these rates were 50% and 29%, respectively, in terms of anxiety and depression and 50% and 31%, respectively, with regard to pain and discomfort.

Enobosarm was also found to be well tolerated, with most of the adverse effects (AEs) being just grade 1 or 2. Grade 3 treatment-related AEs (TRAEs) were reported by 5 patients in the 9-mg cohort (n = 75) and 9 patients in the 18-mg cohort (n = 61); 1 patient in each cohort experienced a grade 4 TRAE. However, no patients on either arm experienced a treatment-emergent AE that resulted in death.

The most frequently reported grade 3 or 4 TRAEs in the 9-mg cohort included increased aspartate aminotransferase (2.7%), hypercalcemia (2.6%), increased alanine aminotransferase (ALT; 1.3%), headache (1.3%), anemia (1.3%), and decreased appetite (1.3%). In the 18-mg cohort, the most commonly experienced grade 3 or 4 TRAEs comprised increased ALT (3.3%), hypercalcemia (3.3%), fatigue (3.3%), and tumor flare (3.3%).

In the phase 3 ARTEST trial, investigators are examining the safety and efficacy of enobosarm compared with exemestane or tamoxifen in the treatment of patients with metastatic, AR-positive/ER-positive/HER2-negative breast cancer who have progressed following treatment with a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK4/6 inhibitor.

References

1. Palmieri C, Linden H, Birrell S, et al. Phase 2 clinical study: efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, in patients with metastatic AR+/ER+ advanced breast cancer resistant to estrogen receptor targeted agents and CDK 4/6 inhibitor in a phase 2 clinical study. Presented at: 2021 ESMO Breast Virtual Congress; May 5-8, 2021; Virtual. Poster 100P.
2. Palmieri C, Linden H, Birrel S, et al. Efficacy and safety of enobosarm, a selective androgen receptor agonist, to target AR in women with advanced AR+/ER+ breast cancer– final results from an international Phase 2 randomized study (G200802). Presented at: 2020 San Antonio Breast Cancer Symposium; December 4-8, 2020; virtual. Abstract PD8-10.