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Androgen Receptor Antagonists May Meet ‘Unmet Need’ in Triple-Negative Breast Cancer



I would encourage your patients with triple-negative breast cancer to seek out this [antiandrogen] approach in the context of clinical trials, so that we can understand the biology better and figure out how best to select patients.
— Tiffany A. Traina, MD

Although there are no androgen receptor antagonists currently approved for the treatment of breast cancer, clinical trials indicate that these agents benefit some patients with triple-negative breast cancer, Tiffany A. Traina, MD, told participants at the 18th Annual Lynn Sage Breast Cancer Symposium in Chicago.1 “I would encourage your patients with triple-negative breast cancer to seek out this approach in the context of clinical trials,” she urged, “so that we can understand the biology better and figure out how best to select patients.”

Dr. Traina is Clinical Director of the Breast Medicine Service and Section Head of the Triple Negative Breast Cancer Clinical Research Program at Memorial Sloan Kettering Cancer Center as well as Assistant Professor of Medicine at Weill Cornell Medicine, New York.

‘Challenging Subtype’

Triple-negative breast cancer—“a very challenging subtype of breast cancer”—is diagnosed in more than 46,000 women each year, “and these tend to be younger women,” Dr. Traina said. “There is a hereditary predisposition and a higher likelihood of BRCA1 [mutation] found in these women,” Dr. Traina explained. “When women do have triple-negative breast cancer, they are at greater risk of recurrence compared to their counterparts with estrogen- or HER2-driven breast cancer. And when those recurrences happen, they happen fast, in the first 2 to 3 years,” Dr. Traina said. Triple-negative breast cancer is “more likely to spread to visceral organs,” she added, “and we even have brain metastases as the site of the first recurrence.”

Effective treatment for triple-negative breast cancer “is one of our real unmet needs,” Dr. Traina stated. The great variety of clinical features and “genetic mutations taking place within triple-negative breast cancers can be “a little bit daunting,” she admitted, but can also provide opportunities “to identify signaling pathways and mutations that may allow us then to target those vulnerabilities within the cell.”

Using Prostate Cancer Drugs

The multicenter TBCRC 011 study provided “proof of concept,” Dr. Traina said, that the androgen receptor antagonist bicalutamide has activity in patients with estrogen receptor–negative (androgen receptor > 10%), progesterone receptor–negative, and androgen receptor–positive metastatic breast cancer. Among the 424 patients with estrogen/progesterone receptor–negative breast cancer, 51 patients (12%) tested androgen receptor–positive, and the 6-month clinical benefit rate was 19%.2 This study met its primary endpoint for efficacy and suggested that the androgen receptor is a relevant target for androgen-driven triple-negative breast cancer.

“There are plenty of drugs that our colleagues in the prostate cancer world use to target the androgen receptor,” Dr. Traina noted. One of those is the CYP17 inhibitor abiraterone (Zytiga). “If we block CYP17, we get a reduction in androgen, and that is great if you are treating prostate cancer. We also have a reduction in downstream estradiol and estrogen. So there is a rationale for thinking about this sort of strategy even in [estrogen receptor]–positive breast cancer,” according to Dr. Traina. “[The androgen receptor] is highly coexpressed in [estrogen receptor]–positive breast cancer, as well as in HER2-positive breast cancer,” she noted.

The phase II UCBG 12-1 trial of abiraterone had results similar to ­TBCRC 011, showing 38% of patients with triple-negative breast cancer screening positive for androgen receptor.3 The clinical benefit rate at 24 weeks was 20%. The adverse effects were similar to when the drug is administered for prostate cancer—fatigue, hypertension, hypokalemia, and nausea. Median progression-free survival was “right around the 3-month mark,’ Dr. Traina reported, “but this is with a hormonal agent as opposed to cytotoxic chemotherapy.”

More Potent Androgen Receptor Antagonist

Another phase II trial tested the androgen receptor antagonist enzalutamide (Xtandi) in women with androgen receptor–positive advanced triple-negative breast cancer.4 Enzalutamide has been approved by the U.S. Food and Drug administration for prostate cancer and is a more potent androgen receptor antagonist that has several mechanisms of action, Dr. Traina reported.

This trial differed from the others in several ways, including the measurement of clinical benefit rate for the primary endpoint at 16 weeks and consideration of any androgen receptor expression as “positive.” By this definition, 79% of triple-negative breast cancer tissue expressed some degree of androgen receptor and 55% of triple-negative breast cancer expressed androgen receptor ≥ 10%.

The 75 evaluable patients reflected the more general triple-negative breast cancer population, Dr. Traina observed. They were younger women, with a median disease-free interval of 2 years. Many of them had visceral disease, and the median number of prior therapies was one, although there was a wide range. The clinical benefit rate at 16 weeks (the primary endpoint) was 35%, and at 24 weeks, it was 29%. This trial reported the first ever objective responses with androgen-directed therapy in triple-negative breast cancer with a confirmed complete or partial response rate of 8%.

“The median progression-free survival in the evaluable popula­tion was around 15 weeks,” Dr. Traina noted. However, androgen receptor by immunohistochemistry alone may not be the optimal biomarker for patient selection; therefore, predictive biomarker discovery was a preplanned correlative embedded in the trial. “Like other hormonal therapies,” she added, “enzalutamide was well tolerated.”

Diagnostic Biomarker Test

As a result of discovery work to identify an expression signature that might better predict response to therapy, a diagnostic test was created and validated. In exploratory analysis with the intent-to-treat population, about 50% were diagnostic biomarker–positive, Dr. Traina said, and these patients stayed on therapy longer and were more likely to have responses.

Progression-free survival was 4 months for biomarker-positive patients vs 2 months for biomarker-negative patients. For patients in the intent-to-treat population who had received 0 to 1 prior therapy, median progression-free survival “is now stretching out to 40 weeks or 9 months” among those who were diagnostic marker–positive, Dr. Traina noted. “In those who were diagnostic marker–negative, median progression-free survival is much shorter—about 2 months.”

She added, “The median overall survival for the entire population was about 1 year.” For patients who were diagnostic biomarker–positive, overall survival was 18 months and not yet reached among those who had received 0 to 1 prior therapy.

Results of this trial “support continued development of enzalutamide in patients with triple-negative breast cancer,” Dr. Traina stated.

Not There Yet

“Is [androgen receptor] therapy ready for prime time? I don’t think we are there just yet,” Dr. Traina concluded. The consistent results from the three studies cited have been encouraging, but “there is a lot still to be sorted out,” she said. “There is correlative work going on in better-biomarker development. There is analysis being done on [androgen receptor] mutations in breast cancer.”

Clinical trials in androgen receptor–positive, triple-negative metastatic breast cancer are testing combinations of bicalutamide and palbociclib (Ibrance; ClinicalTrials.gov identifier NCT02605486), enzalutamide and a PI3K inhibitor (NCT02457910), and a novel CYP17 agent and an androgen receptor antagonist (NCT02580448).

“Whenever we get a signal of something working in advanced disease, we start to move that up a bit earlier. There is an adjuvant study recruiting at Memorial Sloan Kettering that will test enzalutamide for early-stage [androgen receptor]–positive triple-negative breast cancer (NCT02750358). Neoadjuvant enzalutamide is being evaluated in combination with paclitaxel (NCT02689427),” Dr. Traina reported. “There are plenty of novel agents that we are exploring from the prostate cancer world as well,” she added.

“Is there an optimal strategy? This approach is very [similar to] how we approach [estrogen receptor–positive] metastatic breast cancer, beginning with an endocrine approach and then moving on to chemotherapy eventually when needed,” Dr. Traina said. ■

Disclosure: Dr. Traina has received research support to conduct trials with enzalutamide and VT464 and is on the Steering Committee for the Phase III trial of enzalutamide (ENDEAR).

References

1. Traina T: Androgen receptor antagonists: Ready for primetime? 18th Annual Lynn Sage Breast Cancer Symposium. Presented September 23, 2016.

2. Gucalp A, Tolaney S, Isakoff SJ, et al: Phase II trial of bicalutamide in patients with androgen receptor–positive, estrogen receptor–negative metastatic breast cancer. Clin Cancer Res 19:5505–5512, 2013.

3. Bonnefoi H, Grellety T, Tredan O, et al: A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 27:812-818, 2016.

4. Traina T: Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). 2015 ASCO Annual Meeting. Abstract 1003.



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