Enzalutamide Shows Early Promise in AR-Positive TNBC

Tiffany A. Traina, MD

Enzalutamide (Xtandi) demonstrated early signs of efficacy in patients with androgen receptor (AR)-positive triple-negative breast cancer (TNBC), according to findings from the phase II MDV3100-11 study published in the Journal of Clinical Oncology.

A total of 118 patients were enrolled in the single-arm, 2-stage trial, and 78 were evaluable for response. At 16 weeks, the clinical benefit rate (CBR) was 25% (95% CI, 17-33) in the intent-to-treat (ITT) population and 33% (95% CI, 23-45) in the evaluable subgroup. The median progression-free survival (PFS) was 2.9 months (95% CI, 1.9-3.7) in the ITT population and 3.3 months (95% CI, 1.9-4.1) in the evaluable subgroup. Median overall survival (OS) was 12.7 months (95% CI, 8.5 — not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 – not yet reached) in the evaluable subgroup.

“TNBC has the poorest outcomes of the three major subtypes of breast cancer. Attempts to treat TNBC with targeted agents have been met with little success. Modest or no improvements in PFS and OS highlight the high-risk nature of TNBC, as well as the difficulty in identifying relevant targets and effective therapies,” wrote first author Tiffany A. Traina, MD, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, and colleagues.

“Data from this phase II study in a group of patients with AR-positive TNBC support and build upon the findings from others that there seems to exist a subset of patients with androgen-driven TNBC who may benefit from an AR-targeted agent,” added Traina et al. “More than half of the enrolled patients received enzalutamide as their first or second treatment of metastatic disease, highlighting the interest and need for novel, well-tolerated therapies in earlier treatment settings.”

Investigators examined tumor tissue samples collected from June 2013 to June 2014. The data cutoff date for the primary analysis was September 15, 2015.

The primary endpoint was CBR, defined as confirmed complete response (CR), partial response (PR), or stable disease at 16 weeks (CBR16).

Adult patients with an ECOG performance status of 0 to 1 and locally advanced or metastatic AR-positive TNBC were eligible for the study. Patients with ER-positive and/or progesterone receptor-positive primary tumors were eligible if they had advanced TNBC.

Nearly 80% of the evaluable samples expressed nuclear AR >0%, and more than 55% of samples had AR of ≥10%.

Patient demographics and clinical characteristics were consistent between the ITT population and evaluable subgroup. Most patients (84%) received systemic adjuvant treatment for early-stage breast cancer. The median number of prior therapies received for locally advanced or metastatic TNBC was 1 (range, 0-7).

Enrolled patients received 160 mg of enzalutamide once daily until disease progression. Response was assessed every 8 weeks for the first 12 months, then every 12 weeks thereafter using standard radiologic methods. In stage 1, 11 (42.3%) of 26 evaluable patients achieved CBR16, so the study proceeded to stage 2.

Among the first 62 evaluable patients enrolled, 24 (38.7%; 95% CI, 27-52) achieved CBR16, meeting the primary endpoint. Twenty-four (20%; 95% CI, 14-29) patients in the ITT group and 22 patients in the evaluable group (28%; 95% CI, 19-39) achieved CBR at 24 weeks.

One patient in the evaluable subgroup with a metastatic lung lesion achieved a confirmed CR, and 5 achieved a confirmed PR. There was 1 additional confirmed CR reported in the ITT population.

Investigators performed an updated OS analysis after an additional 18 months of follow-up with a data cutoff date of March 15, 2017. Median OS was 12.7 months (95% CI, 8.5-16.5) in the ITT population and 16.5 months (95% CI, 12.7-20.0) in the evaluable subgroup. Median OS in TNBC is generally 12 to 18 months, Traina et al noted.

The median duration of enzalutamide treatment was 8.1 weeks (range, 0.9-87) in the ITT population. Disease progression was the most common reason for discontinuation. Nine patients were still receiving enzalutamide at the time of the data cutoff date.

Eight patients discontinued treatment due to an adverse event (AE). Fatigue (3.4%) was the only treatment-related grade ≥3 AE that occurred in ≥2% of patients.

A quarter of patients reported serious AEs, but those were generally the consequence of progressive metastatic breast cancer and none was considered related to enzalutamide. Twelve patients had grade 5 AEs, 11 of which were related to disease progression. One patient, a 62-year-old woman with a history of tobacco use and hypercholesterolemia, experienced a fatal cardiorespiratory arrest after stent implantation for a myocardial infarction.

Paul Kelly Marcom, MD, associate professor of medicine at Duke University and a member of the Duke Cancer Institute, told OncLive in an interview that, up to now, oncologists thought TNBC did not have a significant steroid-receptor dependency. These results show that there is subset of triple-negative disease that does have such a dependency and that also responds to therapy. He said enzalutamide may be a “new and notable” treatment option for TNBC, especially if researchers can define the subset of triple-negative disease that truly is androgen receptor—dependent.

“There’s a long road between this result and that practice-changing result, but this points in that direction,” he said. “But, as always, you can conceive of some point in the future when we’re able to identify the appropriate triple-negative patients who have androgen receptor dependency who get enzalutamide or some other subsequent agent as part of their adjuvant treatment, just like we use tamoxifen and aromatase inhibitors for estrogen receptor—positive disease. Again, a long way, but the data are there to support that this may be an important addition to the treatment of triple-negative disease.”

Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor—expressing triple-negative breast cancer [published online January 26, 2018]. J Clin Oncol. doi: 10.1200/JCO.2016.71.3495.