Abstract 2549
Background
The androgen receptor (AR) is expressed in ∼ 90% of ER+ BC. Androgen-based therapies have had response rates up to 20-25%, but are not in common use due to poor tissue selectivity, potential aromatization to estrogen, and emergence of ER-targeted agents. RAD140 is an oral nonsteroidal selective AR modulator (SARM) with tissue-selective AR agonist activity in BC cells but attenuated activity in other androgen-responsive tissues. RAD140 inhibited the growth of multiple in vitro and in vivo AR+/ER+ BC models.
Methods
This is a phase 1 study of RAD140 with a 3 + 3 design. The primary objective is safety and to determine the maximum tolerated dose (MTD); secondary objectives are pharmacokinetics and antitumor activity. Key eligibility criteria are: ER+/HER2- and inoperable/metastatic BC (mBC), post-menopausal, and ineligible for standard therapy. AR status is by immunohistochemistry (IHC). Sex hormone-binding globulin (SHBG) and serum prostate specific antigen (PSA) are used to assess AR-engagement.
Results
Dose escalation (n = 16 patients, pts) has been completed. Median age = 58 years, 88% visceral disease, and 94% AR+ by IHC. Median number of prior lines of therapy for mBC = 5; prior fulvestrant 88%, aromatase inhibitor (i) 100%, CDK4/6i 94%, mTORi/PI3Ki 50%, chemotherapy 94%. Dose levels were 50 mg (n = 6), 100 mg (n = 7), and 150 mg (n = 3) QD. Median time on treatment = 8 (range <1-25) wk. The most frequent (>30%) adverse events were elevated ALT/AST, decreased weight/appetite, and constipation. Dose-limiting toxicities (all grade 3 and reversible) were hypophosphatemia (n = 2; 150 mg) and elevated ALT/AST (n = 2; 50 and 100 mg). No drug-related deaths occurred. There was 1 partial response (PR, 100 mg) and 2 pts with stable disease ≥12 wk. The time to PR was 15.9 wk and the duration was 8.6+ wk. SHBG decreased in 12/12 pts and PSA increased in 10/14 pts, most notably in the pt with PR who remains on treatment at 7 mo.
Conclusions
The provisional MTD for RAD140 is 100 mg QD. RAD140 is a novel oral AR-targeted agent for treatment of ER+ mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity. NCT03088527.
Clinical trial identification
NCT03088527.
Editorial acknowledgement
Legal entity responsible for the study
Radius Health, Inc.
Funding
Radius Health, Inc.
Disclosure
E. Hamilton: Advisory / Consultancy: Flatiron Health; Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Clovis Oncology; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Research grant / Funding (institution), Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Sysmex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. N. Vidula: Research grant / Funding (institution): Radius Health; Research grant / Funding (institution): Daewha; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer. C. Ma: Research grant / Funding (self): Eisai; Research grant / Funding (self): Puma; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Syndex; Advisory / Consultancy: Seattle Genetics. R.G. Bagley: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. Z. Yu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M. Annett: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weitzman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M.G. Conlan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weise: Speaker Bureau / Expert testimony: Array BioPharma. All other authors have declared no conflicts of interest.
Resources from the same session
4317 - Prognostic factors analysis of 343 patients with adenocarcinoma of esophagogastric junction
Presenter: Yixun Lu
Session: Poster Display session 2
Resources:
Abstract
4099 - Effects of preoperative preparation time on efficacy of neoadjuvant chemotherapy (SOX) in patients with advanced gastric cancer
Presenter: Xinxin Wang
Session: Poster Display session 2
Resources:
Abstract
3769 - The prognostic value of higher absolute lymphocyte counts for patients with surgically resected non-advanced gastric cancer
Presenter: Se Jun Park
Session: Poster Display session 2
Resources:
Abstract
1718 - Trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy in resectable HER2+ esophageal adenocarcinoma patients: an update on survival and predictive biomarkers in the TRAP study
Presenter: Charlotte Stroes
Session: Poster Display session 2
Resources:
Abstract
5403 - Interim analysis of a phase II trial of perioperative chemotherapy plus avelumab in esophagogastric and gastric adenocarcinoma
Presenter: Thierry Alcindor
Session: Poster Display session 2
Resources:
Abstract
591 - Evaluation of the introduction of primary G-CSF prophylaxis to the FLOT chemotherapy regimen.
Presenter: Kelly-Marie Crampton
Session: Poster Display session 2
Resources:
Abstract
1402 - Subgroup analyses of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with 2 and 4 courses of cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) as neoadjuvant chemotherapy for locally advanced gastric cancer
Presenter: Tsutomu Hayashi
Session: Poster Display session 2
Resources:
Abstract
3743 - HER2 Copy Number as Predictor of Disease-Free Survival in HER2-Positive Resectable Gastric Cancer
Presenter: Zimin Liu
Session: Poster Display session 2
Resources:
Abstract
2032 - Effect of neoadjuvant chemotherapy on the Programmed Death-1 pathway in esophageal and gastric cancer
Presenter: Maria Svensson
Session: Poster Display session 2
Resources:
Abstract
4304 - A user-friendly nomogram to predict relapse-free survival (RFS) in western patients with resected gastric cancer (GC)
Presenter: Massimiliano Salati
Session: Poster Display session 2
Resources:
Abstract