One of the most active areas of research in breast cancer involves the targeting of the androgen receptor. Trials underway for androgen receptor antagonists and modulators, alone and in various combinations of available agents and novel therapies, are yielding encouraging early results.

At the 2017 Miami Breast Cancer Conference, Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, described this promising treatment approach, which may prove relevant for a number of disease subtypes.¹

The majority of hormone receptor–positive tumors express the androgen receptor, as do a moderate number of HER2-positive tumors and nearly one-third of triple-negative breast cancers. Androgen receptor expression seems to be associated with better outcomes in early-stage disease.

Interest in targeting the androgen receptor began with the identification that among several subtypes of triple-negative breast cancer, one had high expression of androgen receptor, a luminal gene-expression pattern, and increased hormone signaling. This luminal androgen receptor subtype has been linked to poor response to chemotherapy.

“The development of selective androgen antagonists [such as bicalutamide and enzalutamide (Xtandi)] paralleled these findings and stimulated interest in the targeted treatment of androgen receptor–positive triple-negative disease,” Dr. Rugo commented.

Triple-Negative Breast Cancer

The phase II TBCRC011 trial included patients who were estrogen receptor–negative, progesterone receptor–negative, and androgen receptor–positive (immunohistochemistry > 10%), with any number of prior lines of therapy.² Of the 424 patients screened, 51 (12%) were androgen receptor–positive. The final study population included 26 patients.

Treatment with bicalutamide (150 mg/d) led to a clinical benefit rate of 19%. In the seven patients who achieved stable disease, five lasted more than 6 months. The number of cycles ranged from 2 to 84. Median progression-free survival was 12 weeks.

What was striking was that some patients responded for a very long time; in fact, some were on androgen receptor–targeted therapy for years.

— Hope S. Rugo, MD

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“What was striking was that some patients responded for a very long time; in fact, some were on androgen receptor–targeted therapy for years,” Dr. Rugo revealed. This trial spurred interest in this approach and in identifying those patients most likely to experience this result. Interestingly, although investigators presumed those would be the luminal androgen receptor subtype, only one luminal androgen receptor patient achieved stable disease. “So it’s not just luminal androgen receptor. It’s more complicated. And this led to future work,” she added.

In a phase II trial, enzalutamide (160 mg/d) was tested in 118 patients with androgen receptor–positive advanced triple-negative breast cancer with any number of prior treatments. Via a different assay that optimized two antibodies, 55% of tumors in this study tested androgen receptor–positive.³ Androgen receptor positivity was any expression (> 0%) by immunohistochemistry, and this definition was applied to the intent-to-treat population (n = 118). The evaluable population, on the other hand, included a subset (n = 75) with androgen receptor ≥ 10% and at least one postbaseline tumor assessment.

In the intent-to-treat population, the clinical benefit rates were 25% at 16 weeks (the primary endpoint) and 20% at 24 weeks. In the evaluable population, the clinical benefit rates were 35% and 29%, respectively. Median progression-free survival was 12.6 weeks in the intent-to-treat group and 14.7 weeks in the evaluable subset.

The researchers applied an androgen-driven genomic signature (PREDICT androgen receptor, now known as Dx), classifying patients as Dx-positive or Dx-negative, and found that biomarker-positive patients had a doubling in progression-free survival. In the subset of patients who had only one prior therapy, Dx-positive patients had a median progression-free survival of 9.3 months, vs 2.0 months for biomarker-negative patients. Overall survival was also doubled in the biomarker-positive group.

“They are very impressive data in this population, who have only chemotherapy as their treatment option,” Dr. Rugo commented.

Resistant Estrogen Receptor–Positive Disease

“Based on new androgen-targeting agents with fewer virilizing effects and more robust, specific inhibition of the production of androgens or the receptor, there’s also been interest in treatment--refractory estrogen receptor–positive disease,” Dr. Rugo stated.

Abiraterone (Zytiga) acetate, an inhibitor of the CYP17A1 enzyme upstream in the steroidogenesis pathway, was tested in a three-arm phase II trial of 293 patients with metastatic estrogen receptor–positive disease, 77% of whom were androgen receptor–positive.⁴ Patients were randomized to receive abiraterone plus prednisone, abiraterone plus prednisone and exemestane, or exemestane alone. No differences were observed in progression-free survival. The lack of activity may be due to the fact that this agent is an androgen receptor inhibitor, not an androgen receptor antagonist, “which might be necessary,” Dr. Rugo suggested.

Abiraterone acetate was also studied in a small study of triple-negative patients (38% with androgen receptor expression ≥ 10%), producing a 24-week clinical benefit rate of 20% at 24 weeks.⁵ Median progression-free survival was less than 3 months, “but activity was suggested,” she added.

Focus of Clinical Trials

“Future directions are interesting in terms of targeting the androgen receptor,” Dr. Rugo noted. She cited a number of clinical trials that are recruiting or ongoing to evaluate various agents in androgen receptor–positive patients. Correlative studies are also examining androgen receptor biomarkers and androgen receptor–mutation analyses, to decipher which patients might benefit most. (The ClinicalTrials.gov identifier numbers are in parentheses.)

Androgen Receptor–Positive Triple-Negative Metastatic Disease:

• Phase III three-arm ENDEAR trial in Dx-positive patients: 780 patients randomized to receive enzalutamide, paclitaxel, or the combination (NCT02929576)
• Phase II study of bicalutamide plus palbociclib (Ibrance), which might enhance bicalutamide’s effect (NCT02605486)
• TBCRC032 trial of enzalutamide with or without a phosphoinositide 3-kinase inhibitor inhibitor (NCT02457910; currently on hold due to toxicity concerns)
• Phase II trials of GTx-024, a selective androgen receptor modulator, and also in estrogen receptor–positive patients (NCT02368691, NCT02971761)
• Feasibility trial of enzalutamide in stage I-III disease (NCT02750358)
• Neoadjuvant enzalutamide plus paclitaxel (NCT02689427)

Hormone Receptor–Positive Metastatic Breast Cancer:

• Exemestane with or without enzalutamide (NCT02007512)
• Phase II trials of GTx-024 (NCT02746328, NCT02463032)
• Phase I/II trial of VT454, a lyase-selective inhibitor of CYP17 (NCT02580448)
• Phase II trial of TAK-700 (orteronel), a nonsteroidal CYP17A1 inhibitor (NCT01990209; also being studied in triple-negative disease)
• SAKK 21/12, a phase II trial of CR1447 transdermal CR1447 (4-hydroxytestosterone; NCT02067741; also being studied in triple-negative disease)

HER2-Positive Metastatic Breast Cancer:

• Phase II trial of enzalutamide plus trastuzumab (NCT02091960). ■

DISCLOSURE: Dr. Rugo disclosed relationships (through her institution) with GlaxoSmithKline, Genentech/Roche, Novartis, Pfizer, Merck, Amgen, Eisai, Plexxikon, Macrogenics, Lilly, OBI, BioMarin, and Genomic Health.

REFERENCES

1. Rugo H: Targeting the androgen receptor in breast cancer. 2017 Miami Breast Cancer Conference. Invited Lecture. Presented March 11, 2017.

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. Traina TA, Miller K, Yardley DA, et al: Results from a phase 2 study of enzalutamide, an androgen receptor inhibitor, in advanced AR+ triple-negative breast cancer. 2015 ASCO Annual Meeting. Abstract 1003.

4. O’Shaughnessy J, Campone M, Brain E, et al: Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Ann Oncol 27:106-113, 2016.

5. 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.