The largest prospective trial to date of androgen blockade in advanced triple-negative breast cancer (TNBC) has demonstrated positive clinical activity using the prostate cancer drug enzalutamide (Xtandi, Medivation/Astellas Pharma) to target tumors expressing the androgen receptor (AR).
Published online in the Journal of Clinical Oncology, the phase II analysis met its primary endpoint, showing a clinical benefit rate (CBR) of 25% at 16 weeks in the overall intent-to-treat (ITT) group (95% CI 17%-33%) and 33% in a subgroup (95% CI 23%-45%).
Attempts to use targeted therapy to treat this poor-prognosis breast cancer subtype, described in 2005, have experienced little success, showing modest or no improvements in progression-free and overall survival (PFS, OS), noted the investigators, led by Tiffany Traina, MD, of Memorial Sloan Kettering Cancer Center in New York City. Mounting research suggests that this AR antagonist, used in castration-resistant prostate cancer, may be the answer to an unmet treatment need in a subgroup of TNBC, which has the worst outcome of all three major breast cancer types. Interest has been growing in this targeted approach, as MedPage Today reported last year.
“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,” Traina and co-authors wrote.
With tumor sample collection begun in 2013, the 2-year study originally enrolled 118 patients with locally advanced or metastatic TNBC from 45 sites in seven countries. The mean age of patients was 57 years, and 77% were white. TNBC was defined as <1% staining for estrogen and progesterone receptor and for human epidermal growth factor receptor 2, 0, or 1+ by immunochemistry (IHC) staining or negative by in situ hybridization.
An IHC assay, optimized with two AR antibodies for breast rather than prostate cancer, tested tumor samples, with any nuclear AR staining greater than 0% considered positive. A subgroup consisting of patients with tumors expressing at least 10% nuclear AR was also identified. Nearly 80% of samples expressed nuclear AR of of more than 0%, while 5 5% had AR of 10% or more. All patients received enzalutamide 160 mg once daily until disease progression, with a median duration of treatment of 8.1 weeks.
In secondary study endpoints, median PFS was 2.9 months (95% CI 1.9-months) in the ITT population and 3.3 months (95% CI 1.9-4.1 months) in the evaluable subgroup. Median OS at 18 months’ follow-up was 12.7 months (95% CI 8.5 to 16.5) in the ITT population and 16.5 months (95% CI 12.7-20) in the evaluable >10% subgroup. Complete or partial response was observed in 8% of subgroup and 6% of ITT patients.
“Treatment targeting AR has been studied in TNBC now for several years, so it is not completely novel, Hope S. Rugo, MD, of University of California San Francisco Hellen Diller Family Comprehensive Cancer Center (and not involved in the study), told MedPage Today. “What is novel is this drug itself, which appears to be a more potent antagonist of AR.”
In terms of safety, enzalutamide was well tolerated, with adverse events well within the drug’s known profile. Eight patients stopped treatment because of some adverse event. The only treatment-related grade 3 or higher adverse event occurring in more than 2% was fatigue.
Last year, a phase I/Ib study by Traina’s group reported positively on the safety of enzalutamide alone or combined with endocrine therapies in advanced breast cancer. And, in the past few years, positive antitumor activity with AR inhibition has also been reported in two prospective phase II AR-positive breast cancer trials of two other antagonists, bicalutamide (Casodex) with a 6-month CBR of 19%, and abiraterone acetate (Zytiga) combined with prednisone, with a 6-month CBR of 20%.
Compared with bicalutamide, the authors pointed out, enzalutamide has no known AR agonist activity and has proven superior to bicalutamide in phase II prostate cancer studies. As for abiraterone acetate, it requires concomitant prednisone, which stimulates the glucocorticoid receptor, expressed in approximately 25% of TNBCs and possibly stimulative of tumor growth. The drug also increases progesterone, potentially stimulating the progesterone receptor even at the low levels seen in TNBC.
According to the authors, their findings support the need for “novel, well-tolerated therapies administered in earlier treatment settings.”
Added Rugo, “AR blockade is overall well tolerated, and it is likely that response will be better if it is used earlier, before additional mechanisms of resistance develop.” Another advantage of earlier treatment is that patients may be able to start with oral medication. “Quality of life is better than with chemotherapy, so a trial in an appropriate patient early in the course of metastatic disease seems reasonable,” Rugo said.
In the meantime, oncologists are awaiting data on a potential gene signature to identify precisely the patients most likely to benefit from AR inhibition. “Overall we expect that, at most, 10% of patients with TNBC both have AR positive-disease and are candidates for a treatment like enzalutamide, and of those about 25% appear to benefit,” said Rugo. “We don’t as yet have a reliable and definitive test for AR expression that correlates with response, but work is ongoing to identify gene signatures that may be a better marker of responsiveness. If these data become available, we will be better placed to study enzalutamide either as a single agent compared with standard therapy or in rationale combinations.”
In Rugo’s view, the data from Traina and colleagues suggest that enzalutamide may be the most active agent to date in this setting. “Regardless, AR antagonists are potential therapy for a very small number of patients with AR-positive TNBC, she said. She noted that newer AR antagonists are under study and that larger, more definitive studies are expected to shed further light in this area of treatment.
As a possible study limitation, the authors cited the suboptimal performance of IHC as a treatment-guiding and potentially predictive assay. In 2017, Kumar et al reported a threshold of >10% nuclear expression had a positive predictive value of AR of only 30%, which may restrict clinical application. “This is a critical consideration in the development of a treatment-associated assay, because one would not want to exclude patients from receiving a potentially beneficial and well-tolerated treatment,” Traina and associates wrote.
Supported in part through National Institutes of Health/National Cancer Institute Cancer Center and by Medivation, a Pfizer company, and Astellas Pharma, co-developers of enzalutamide.
Lead author Traina disclosed ties to Genentech, Eisai, Mundipharma, Pfizer, AstraZeneca, Bayer, Immunomedics, Merck, Medivation, Celgene, Innocrin Pharma, Genomic Health Research Funding, Astellas Pharma, Eisai, Pfizer, Novartis, Innocrin Pharma, and AstraZeneca.