Androgen Receptor Antagonists Approach Primetime for Breast Cancer

Tiffany A. Traina, MD

Though not yet ready for primetime, existing data for androgen receptor (AR) antagonists are encouraging and future results could move these agents into the treatment paradigm for large populations of patients with breast cancer, according to Tiffany A. Traina, MD, at the 2016 Lynn Sage Breast Cancer Symposium.

Triple-negative breast cancer (TNBC), which is a heterogeneous disease, houses a group of patients who may benefit from AR antagonists. “There is a subset—that is larger than we initially thought—that upwards of almost 50% women with triple-negative breast cancer may have this androgen-driven subtype,” Traina, from the Memorial Sloan Kettering Cancer Center (MSK), said in an interview withTargeted Oncology. “We now have 3 phase II studies that show signal of activity for targeting androgen in that subset.”

Bicalutamide

The first agent described by Traina was bicalutamide, which was first approved in 1995 to treat prostate cancer. This agent was evaluated in the phase II TBCRC011 trial for patients with AR-positive, ER/PR-negative metastatic breast cancer.¹

Twenty-six patients on the TBCRC011 trial were AR-positive (immunohistochemistry [IHC] >10%) and received bicalutamide at 150 mg daily. The primary endpoint on the trial was clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD] >24 weeks). Though there were no CRs or PRs on the trial, 19% (95% CI; 7-39) of patients (n = 5) had SD for at least 6 months. An additional 8% of patients (n = 2) had SD of less than 6 months.

In a whole transcriptome analysis of the results presented at the 2014 San Antonio Breast Cancer Symposium,²Traina and her colleagues came to several conclusions: (1) RNA expression variation was consistent with basal-like breast cancer, (2) AR-positive tumors were noted beyond the luminal AR subtype, and (3) there was clinical benefit seen beyond the luminal AR subtype.

Overall, Traina said in her presentation, TBCRC011 was proof-of-concept that bicalutamide had activity in AR-positive metastatic TNBC. An ongoing study at MSK is looking at the agent in combination with the CDK4/6 inhibitor palbociclib for women with AR-positive metastatic breast cancer (NCT02605486).

Abiraterone Acetate

The second-generation AR inhibitor abiraterone acetate (Zytiga) was evaluated in a phase II trial of postmenopausal women with ER-positive metastatic breast cancer.³A total of 297 patients were randomized to receive abiraterone and prednisone (n = 89) ; abiraterone, prednisone, and exemestane (n = 106); or exemestane alone (n = 102). The primary endpoint of the trial was progression-free survival (PFS).

Trial data showed that while overall response rate (ORR) was higher among those receiving abiraterone, prednisone, and exemestane (12.1%) compared with exemestane alone (6.3%), the benefit was not statistically significant (P= .366). Similarly, the clinical benefit rate was higher with abiraterone, prednisone, and exemestane (22.7%) compared with exemestane (12.7%), but again the data were not statistically significant (P= .137).

The median PFS with exemestane alone was 3.7 months, compared with 4.5 months with abiraterone, prednisone, and exemestane (HR, 0.96; 95% CI, 0.70-1.32;P= .795) and 3.7 months with abiraterone plus prednisone (HR, 1.1; 95% CI, 0.82-1.60;P= .437).

Enzalutamide

Most recently, enzalutamide (Xtandi) was evaluated in the phase II MDV3100-11 trial presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.⁴In this study, single agent enzalutamide was evaluated in patients with advanced AR-positive (IHC ≥ 10% and ≥ 1 post-baseline tumor assessment) TNBC. The primary endpoint of the trial—the largest prospective trial of an AR inhibitor in TNBC—was clinical benefit rate at 16 weeks.

Among the 75 evaluable patients at a median age of 50 years, the CBR was 35% (n = 26) at 16 weeks (95% CI, 24-46) and was 29% (n = 22) at 24 weeks (95% CI, 20-41). Further, 6 patients had a CR or PR (response rate, 8%) and median PFS was 14.7 weeks in the evaluable population (95% CI, 8.1-19.3).

In the intent-to-treat population (n = 118; those who received ≥1 dose of enzalutamide), the median age of patients was 57 years. The 16-month CBR was 25% and the 24-month CBR was 20%. The response rate was 6%. Median PFS was 12.6 weeks. Median overall survival was 12 months.

Using the PREDICT AR biomarker test, the median PFS was 16.1 weeks in the positive group versus 8.1 weeks in the negative arm. In those who received 0-1 prior therapies, the median PFS was 40.4 weeks in patients with PREDICT AR-positive tumors versus 8.9 weeks in those with negative tumors.

Overall, 61% of patients (n = 72) experienced a treatment-related adverse event (AE) with 1 AE being serious. The most common related AEs were fatigue (30%), nausea (22%), and decreased appetite (11%).

Enzalutamide, Traina said, is the most promising agent in this space and is currently being explored in a “definitive” phase III trial (named ENDEAR), which will evaluate the agent in combination with paclitaxel or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC.

Outside of that, there are other trials in metastatic TNBC evaluating enzalutamide with or without a PI3K inhibitor (NCT02457910); a novel CYP17 inhibitor and AR antagonist (NCT02580448); and a phase II study of GTx-024 (NCT02368691). In the adjuvant setting, enzalutamide is being evaluated in a feasibility study (NCT02750358) and in the neoadjuvant setting with paclitaxel (NCT02689427).

Traina emphasized that an AR antagonist could make a huge difference to patients’ quality of life. “Using a hormonal strategy versus what chemotherapy is so much easier for our patients,” she said. “The side effect profile for taking a hormone pill a day where you don't lose your hair, you're not sick to your stomach, you're not vulnerable to infection—it's really great quality of life.”

References

1. 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. 2013 Oct 1;19(19):5505-12. doi: 10.1158/1078-0432.CCR-12-3327. Epub 2013 Aug 21.
2. Traina TA, Gulcap A, Polkinghorn W, et al. Whole transcriptome analysis of AR+ ER/PR- metastatic breast cancers treated with bicalutamide on TBCRC011. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract P3-04-01.
3. O'Shaughnessy J Campone M, Brain E, et al. Randomized phase 2 study of abiraterone acetate (AA) with or without exemestane (E) in postmenopausal patients (pts) with estrogen receptor—positive (ER+) metastatic breast cancer (MBC).J Clin Oncol32:5s, 2014 (suppl; abstr 519).
4. Traina TA, Miller K, Yardley DA, et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC).J Clin Oncol33, 2015 (suppl; abstr 1003)