Background: Historically, androgens have been utilized for the treatment of BC as the androgen receptor (AR) is the most highly expressed steroid receptor (∼95% in estrogen receptor positive (ER+), ∼50% in ER negative). However, steroidal androgens often exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), GTx-024, offers a targeted approach of AR activation in ER+/AR+ BC without virilization or estrogenic effects. A previous Phase 2 study of 9 mg GTx-024 in MET ER+ BC demonstrated proof-of-concept, with 6/17 ER+/AR+ patients (pts) exhibiting clinical benefit (CB) following 6 months (m) of treatment. Increasing the dose to 18 mg has the potential for greater efficacy without compromising safety.

Trial Design: Open label, multinational, randomized, parallel design Phase 2 study to assess the efficacy and safety of GTx-024 in PM ER+/AR+ BC. Pts will be randomized to receive GTx-024, 9 mg or 18 mg orally (PO) daily. Therapy continues until disease progression. Pts achieving a CB can be treated for 12 m following the initiation of study treatment; those demonstrating continued CB are offered continuation in a safety extension study under a separate protocol.

Eligibility Criteria:

Inclusion: Informed consent, female, ≥18 years (yr), PM, MET or LA ER+ (≥1% staining) BC, HER2 negative, ≥1 prior hormonal treatment for BC (≥6 m response for MET; ≥3 yr response for adjuvant), provide archived tumor tissue for AR determination, measurable or bone-only disease, evidence of PD within 30 days (d), ECOG 0 or 1.

Exclusion: >1 prior chemotherapy regimen for MET, uncontrolled CNS metastases, radiotherapy ≤14d prior to enrollment, major surgery ≤28d prior to enrollment, currently receiving hormone replacement, hepatitis B/C positive, HIV positive, another active cancer.

Specific Aims: Primary endpoint: proportion of AR+ pts in each arm achieving a CB response (CBR) at 24 weeks (wks). CBR defined as pts with a complete response (CR), partial response (PR), or stable disease (SD); per modified RECIST 1.1. Secondary endpoints: objective response rate, progression free survival, time to progression, and duration of response.

Statistical Methods: Simon's two-stage (optimal) design will be used to assess primary efficacy, requiring up to 88 evaluable pts; i.e., pts with centrally confirmed AR+ who receive at least one dose of study drug. The trial will test for an unacceptably low CBR of ≤10% versus a CBR ≥30%. There is no intent to statistically compare the two dose arms, but to determine whether either or both doses result in an acceptable CBR.

Target Accrual: Up to 118 pts will be enrolled. The first stage will be assessed in each arm among the first 18 evaluable pts. If at least 3/18 exhibit CB at 24 wks, then the arm will proceed to the second stage of recruitment up to a total of 44 pts. Otherwise, the arm will be discontinued for lack of efficacy.

Trial Information:

Citation Format: Overmoyer B, Rugo H, Schwartzberg L, Palmieri C, Taylor R, Hancock M, Small S, Johnston MA. Phase 2 open label, multinational, randomized, parallel design study investigating the efficacy and safety of GTx-024 on metastatic (MET) or locally advanced (LA) ER+/AR+ breast cancer (BC) in postmenopausal (PM) women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-06.