8 TiP Randomized, Multicenter, Phase 3 Study to Evaluate the Combination of Enobosarm and Abemaciclib Compared With Estrogen-Blocking Agent for the Second-Line Treatment of AR+, ER+, HER2– Metastatic Breast Cancer in Patients Who Have Previously Received Palbociclib and an Estrogen-Blocking Agent Combination Therapy

Background/Significance

Targeting the androgen receptor (AR) may be the next important endocrine therapy for women with advanced breast cancer. AR, the most abundantly expressed steroid receptor in breast cancer, has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR-targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials and 1450 dosed subjects including in 2 phase 2 studies conducted in women (158 subjects) who had AR+, estrogen receptor–positive (ER+), HER2-negative metastatic breast cancer (mBC). An open-label, parallel-design phase 2 study was conducted in women with heavily pretreated ER+, HER2- metastatic breast cancer who were randomized to oral daily enobosarm at a dose of 9 mg or 18 mg. The evaluable group (EE) were patients who were AR-positive (> 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy plus a CDK4/6 inhibitor. Subsequent treatment with enobosarm in this cohort resulted in a clinical benefit rate of 50%, and the best objective response rate (ORR) was 30% (2 complete responses and 1 partial response). Of the 10 patients, 7 had AR nuclei staining of 40% or greater, which included the 3 patients who achieved partial and complete disease responses to enobosarm. None of the 3 patients in this cohort with AR nuclear staining less than 40% responded to enobosarm. Although in a small subset of the entire study, it appears that enobosarm monotherapy had activity in patients who had 40% or greater AR staining and who had progressed on standard endocrine therapy with a CDK4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements.

Design and Methods

The phase 3 ENABLAR-2 trial is a multicenter, randomized, open-label, 2 treatment–arm efficacy and safety study. Patients are being randomized to 2 treatment arms in a 1:1 fashion. If first-line therapy for mBC was a nonsteroidal aromatase inhibitor (AI) plus palbociclib (Ibrance), then the patient is randomized to either enobosarm plus abemaciclib (Verzenio) or fulvestrant. If first-line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient is randomized to either enobosarm plus abemaciclib or an AI (steroidal or nonsteroidal). The key objectives are to determine the safety and efficacy of the enobosarm and abemaciclib combination versus an alternative estrogen blocking agent in the treatment of AR+, ER+, HER2-negative (AR% nuclei staining ≥ 40%) mBC with a primary end point of imaging progression-free survival. Secondary end points include objective response rate, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ), and change in body composition as measured by dual-energy x-ray absorptiometry (DEXA).

Status

The study is currently ongoing, and it is anticipated that enrollment will be completed this year.

Author Affiliations:

Elgene Lim,¹ Adam Brufsky,² Hope S. Rugo,³ Charles Vogel,⁴ Joyce A. O’Shaughnessy,⁵ Robert H. Getzenberg,⁶ K. Gary Barnette,⁶ Domingo Rodriguez,⁶ Mitchell Steiner,⁶ Hannah Linden⁷

¹University of New South Wales, Australia; Garvan Institute of Medical Research, Darlinghurst, Australia

²Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA

³University of California, San Francisco, San Francisco, CA

⁴Miami Cancer Institute, Baptist Health, Miami, FL

⁵Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX

⁶Veru Inc, Miami, FL
⁷University of Washington/Seattle Cancer Care Alliance, Seattle, WA